Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, The University of Texas El Paso, El Paso, TX 79968, United States.
Department of Biological Sciences, The University of Texas El Paso, TX 79968, United States; The Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX 79968, United States.
J Control Release. 2023 Sep;361:314-333. doi: 10.1016/j.jconrel.2023.08.005. Epub 2023 Aug 10.
Solid tumors are abnormal mass of tissue, which affects the organs based on its malignancy and leads to the dysfunction of the affected organs. The major problem associated with treatment of solid tumors is delivering anticancer therapeutics to the deepest layers/core of the solid tumor. Deposition of excessive extracellular matrix (ECM) hinders the therapeutics to travel towards the core of the tumor. Therefore, conventional anticancer therapeutics can only reduce the tumor size and that also for a limited duration, and tumor recurrence occurs once the therapy is discontinued. Additionally, by the time the cancer is diagnosed, the cancer cells already started affecting the major organs of the body such as lung, liver, spleen, kidney, and brain, due to their ability to metastasize and lung is the primary site for them to be infiltrated. To facilitate the anticancer therapeutics to penetrate the deeper layers of tumor, and to provide concurrent treatment of both the solid tumor and metastasis, we have designed and developed a Bimodal Light Assisted Skin Tumor and Metastasis Treatment (BLAST), which is a combination of photothermal and chemotherapeutic moieties. The BLAST is composed of 2D boron nitride (BN) nanosheet with adsorbed molecules of BCL-2 inhibitor, Navitoclax (NAVI) on its surface, that can breakdown excessive ECM network and thereby facilitate dissociation of the solid tumor. The developed BLAST was evaluated for its ability to penetrate solid tumors using 3D spheroids for the uptake, cytotoxicity, growth inhibition, reactive oxygen species (ROS) detection, penetration, and downregulation of proteins upon laser irradiation. The in vivo therapeutic studies on a skin cancer mice model revealed that the BLAST with and without laser were able to penetrate the solid tumor, reduce tumor volume in mice, dissociate the protein network, and prevent lung metastasis as confirmed by immunohistochemistry and western blot analysis. Post analysis of serum and blood components revealed the safety and efficacy of BLAST in mice. Hence, the developed BLAST holds strong promise in solid tumor treatment and metastasis prevention simultaneously.
实体瘤是一种异常组织肿块,它会根据其恶性程度影响器官,并导致受影响器官的功能障碍。治疗实体瘤的主要问题是将抗癌治疗药物递送到实体瘤的最深层/核心。过多的细胞外基质(ECM)的沉积阻碍了治疗药物向肿瘤核心的输送。因此,传统的抗癌治疗药物只能减少肿瘤的大小,而且这种效果也是有限的,一旦停止治疗,肿瘤就会复发。此外,由于癌症细胞具有转移的能力,当癌症被诊断出来时,它们已经开始影响身体的主要器官,如肺、肝、脾、肾和脑,而肺部是它们最先入侵的部位。为了促进抗癌治疗药物渗透到肿瘤的更深层,并为实体瘤和转移瘤同时提供治疗,我们设计并开发了一种双模态光辅助皮肤肿瘤和转移治疗(BLAST),它是光热和化疗部分的组合。BLAST 由二维氮化硼(BN)纳米片组成,其表面吸附有 BCL-2 抑制剂 Navitoclax(NAVI)的分子,可以分解过多的 ECM 网络,从而促进实体瘤的解离。通过 3D 球体评估了开发的 BLAST 穿透实体瘤的能力,用于摄取、细胞毒性、生长抑制、活性氧(ROS)检测、穿透和激光照射后蛋白质的下调。在皮肤癌小鼠模型中的体内治疗研究表明,BLAST 无论是否进行激光照射,都能够穿透实体瘤,减少小鼠的肿瘤体积,分解蛋白质网络,并通过免疫组织化学和 Western blot 分析预防肺转移。对血清和血液成分的后分析表明,BLAST 在小鼠中的安全性和疗效。因此,开发的 BLAST 具有同时治疗实体瘤和预防转移的巨大潜力。
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